1. Field of the Invention
The present invention relates to an improved method for synthesizing 1-(tetrahydro - 2-furanyl) - 5-fluorouracil.
2. The Prior Art
The synthesis of 1-(tetrahydro - 2-furanyl) -5-fluorouracil has been reported in the literature and is the subject of at least one patent by Solomon A. Giller (British Patent No. 1,168,391). The method of synthesis disclosed by Giller involves, in part, the use of mercury compounds of uracils; however, the synthesis method of interest herein is that set forth in examples 8 and 9 on page 4 of the above British patent.
In example 8, 5-fluorouracil and chlorotrimethylsilane are stirred in the presence of triethylamine in dry toluene. The precipitated triethylamine hydrochloride is filtered off and the filtrate is concentrated and reacted with 2-chlorofuranidine to produce 1-(tetrahydro - 2-furanyl) - 5-fluorouracil. In example 9, Hexamethyldisilazane is used in place of the chlorotrimethylsilane of example 8. In both example 8 and 9 above, hydrogen chloride is produced as a by-product of the reaction and tends to cleave certain bonds of the starting material, bis-trimethylsilyl -5-fluorouracil, and the product, 1-(tetrahydro 2-furanyl) - 5-fluorouracil, thus acting as one of the contributory factors for the relatively low percentages of theoretical yields 50% and 65%, respectively.
The product of interest herein, 1-(tetrahydro - 2-furanyl) - 5-fluorouracil, has been reported as an anti-metabolite which possesses a relatively high therapeutic index (approximately two times that of 5-fluorouracil) and low toxicity (approximately 5 to 6 times less than 5-fluorouracil) toward cancer of the breast and gastrointestinal tract. See "The Synthesis of 1-(tetrahydro -2-furanyl) -5-fluorouracil (Ftorafur) via Direct Fluorination", R. A. Earl and L. B. Townsend, Journal of Heterocyclic Chemistry 9, 1141 (1972).
Due to the interest in this particular compound, it has been synthesized as set forth in the British patent, as previously discussed, and also by an alternate synthesis route using the direct fluorination of 1-(tetrahydro - 2-furanyl) uracil as set forth in the above publication of Earl and Townsend. The former synthetic route results in relatively low yields and the latter synthetic route involves the use of a gas, trifluoromethylhypofluorite, which is highly reactive, with a number of potential hazards. Extreme difficulties in scaling up the latter process, to produce large quantities of 1-(tetrahydro -2-furanyl) - 5-fluorouracil may thus be encountered. Scale up will be desirable if this compound successfully passes the necessary tests to thereby be accepted as an approved chemotherapeutic agent against certain forms of cancer.
Accordingly, it would be a significant advance in the art to provide an improved method of synthesizing 1-(tetrahydro - 2-furanyl) - 5-fluorouracil from commercially available compounds. The present invention provides this advance.